Research ArticleNEUROIMMUNOLOGY

T cell engagement of cross-presenting microglia protects the brain from a nasal virus infection

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Science Immunology  05 Jun 2020:
Vol. 5, Issue 48, eabb1817
DOI: 10.1126/sciimmunol.abb1817

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Safeguarding the sense of smell

Given the proximity of the olfactory bulb to the upper airways, it is surprising that viruses that infect the upper airways, including influenza, rarely infect the brain. In mice, intranasal infection with vesicular stomatitis virus (VSV) does result in infection of sensory neurons in the olfactory bulb. Using VSV that expresses a fluorescent reporter, Moseman et al. examined the ability of VSV to infect distinct cell types within olfactory bulb. Although VSV infection was restricted to neurons within the olfactory bulb, they found that microglial cells that were not infected by VSV to be the key in priming T cell responses that promoted viral clearance.

Abstract

The neuroepithelium is a nasal barrier surface populated by olfactory sensory neurons that detect odorants in the airway and convey this information directly to the brain via axon fibers. This barrier surface is especially vulnerable to infection, yet respiratory infections rarely cause fatal encephalitis, suggesting a highly evolved immunological defense. Here, using a mouse model, we sought to understand the mechanism by which innate and adaptive immune cells thwart neuroinvasion by vesicular stomatitis virus (VSV), a potentially lethal virus that uses olfactory sensory neurons to enter the brain after nasal infection. Fate-mapping studies demonstrated that infected central nervous system (CNS) neurons were cleared noncytolytically, yet specific deletion of major histocompatibility complex class I (MHC I) from these neurons unexpectedly had no effect on viral control. Intravital imaging studies of calcium signaling in virus-specific CD8+ T cells revealed instead that brain-resident microglia were the relevant source of viral peptide–MHC I complexes. Microglia were not infected by the virus but were found to cross-present antigen after acquisition from adjacent neurons. Microglia depletion interfered with T cell calcium signaling and antiviral control in the brain after nasal infection. Collectively, these data demonstrate that microglia provide a front-line defense against a neuroinvasive nasal infection by cross-presenting antigen to antiviral T cells that noncytolytically cleanse neurons. Disruptions in this innate defense likely render the brain susceptible to neurotropic viruses like VSV that attempt to enter the CNS via the nose.

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